In a 2nd presentation seeking at new methods of dealing with non-small cell lung cancer (NSCLC) that has both the EGFR and T790M mutations, scientists tod the 26th EORTC-NCI-AACR1 Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, that an oral drug known as ASP8273 has triggered tumor shrinking in sufferers in a phase I clinical study in Japan.
Mutations of the epidermal growth factor (EGFR) take place in about 30-35% of Asian subjects with NSCLC (and in 10-15% of Caucasian patients). EGFR inhibitors known as tyrosine kinase inhibitors (TKI)2, like as erlotinib, gefitinib and afatinib, can be applied to treat EGFR-mutated NSCLC. On the other hand, these sufferers will gradually develop level of resistance to EGFR TKI treatment, rendering their disease resistant to present therapies. A additional mutation known as T790M accounts for 60% of this obtained resistance.
ASP8273 is a novel drug that prevents the EGFR mutation and the T790M resistance mutation. Previously research in mice had proven that it triggered NSCLC to disappear entirely, and so a phase I clinical study was began in January 2014 to evaluate the drug’s safety and effectiveness in humans.
Twenty-four Japanese sufferers have registered so far to get one of six levels of doses (25, 50, 100, 200, 400 and 600mg) once daily. A additional seven subjects have been registered into a 2nd group to assess doses of 100mg, 200mg and 400mg a day (a dose escalation study), and the scientists are preparing to take a total of 124 sub.jects Cancer had developed in all the sufferers after prior therapy with EGFR TKI therapy, and the majority of them had the T790M mutation.
Dr Haruyasu Murakami, told the meeting: “Initial success from this research show a high entire response rate of 78%, with tumours reducing in 7 out of 9 sufferers who had both the EGFR and T790M mutations. While the number of sufferers is still small, this reaction is comparable with two other medicines in development that focus on EGFR – CO-1689 and AZ-9291 – but ASP8273 has fewer safety issues than these drugs.”
The very frequent adverse reactions to ASP8273 were mild cases of diarrhoea (in 50% of the subjects), nausea and vomiting (in a 75% of the subjects). There were not one of the serious respiratory issues, heart issues and high blood sugar levels that have took place while in the clinical studies of the other two medicines. One sufferer getting 400mg a day suffered diarrhoea that was serious enough for the dose to be decreased. The 4 sufferers who obtained 600mg a day had dose-limiting toxicities which include severe diarrhoea, colitis (inflammation of the colon) and cholangitis (infection of the bile duct). All the sufferers in the study who had the T790M mutation stay in the trial without additional progression of their disease.
“These details recommend that ASP8273 would be estimated to have possible clinical advantages with less adverse side-effects in comparison to CO-1689 and AZ-9291,” Dr Murakami said.
The scientists are ongoing to hire sufferers to the phase I dose escalation trials. “We anticipate a recommended dose for a phase II study to be identified soon and then we will begin hiring sufferers with both EGFR and T790M mutations instantly in Japan and other Asian nations. At present we are monitoring partial reactions in subjects receiving the 100mg dose and they are tolerating it well,” he will conclude.
Professor Jean-Charles Soria, stated: “ASP8273 is the 4th EGFR-mutant specific kinase inhibitor in advancement for NSCLC sufferers with obtained resistance to EGFR inhibition relevant to overall look of the T790M mutation. Activity is obviously promising and toxicity is in line with the expected mechanism of action, but figures are small and follow-up is quite immature at the moment.”